Functionalized heterocyclic compounds as antiviral agents

Abstract

The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, thereof:which inhibit the protein(s) encoded by hepatitis B virus (HBV) or interfere with the function of the HBV life cycle of the hepatitis B virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HBV infection. The invention also relates to methods of treating an HBV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

What is claimed: 
     
       1. A compound represented by Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, N-oxide, ester or prodrug thereof, wherein:
 Q 1 , Q 2 , Q 3 , and Q 4  are each independently selected from hydrogen, halo, —NR 11 R 12 , optionally substituted —C 1 -C 6  alkyl, optionally substituted —C 2 -C 6  alkenyl, optionally substituted —C 1 -C 6  alkoxy, optionally substituted —C 3 -C 8  cycloalkyl; optionally substituted —C 3 -C 8  cycloalkenyl; optionally substituted 3- to 8-membered heterocycloalkyl; optionally substituted aryl; and optionally substituted heteroaryl; 
 provided that at least one of Q 3  and Q 4  is not hydrogen; 
 Y 1  is hydrogen, halo, optionally substituted C 1 -C 6  alkyl, optionally substituted —C 3 -C 6  cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, —CN, —C(O)R 11 ; —C(O)OR 11 ; —C(O)N(R 11 )(R 12 ); —C(O)N(R 11 )S(O) 2 (R 12 ); —S(O) 2 R 11 ; or —S(O) 2 N(R 11 )(R 12 ); 
 Y 2  is hydrogen, halo, optionally substituted C 1 -C 6  alkyl, optionally substituted —C 3 -C 6  cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, —CN, —C(O)R 11 ; —C(O)OR 11 ; —C(O)N(R 11 )(R 12 ); —C(O)N(R 11 )S(O) 2 (R 12 ); —S(O) 2 R 11 ; —S(O) 2 N(R 11 )(R 12 ), or —O—Si(R 11 ) 3 ; 
 Y 3  is —C(O)R 11 , —COOR 11 , —C(O)NHSO 2 R 11 , —C(O)NHSO 2 NR 11 R 12 , or 1,2,4-oxadiazol-3-yl-5(4H)-one, or Y 3  is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —C 5 -C 6  cycloalkyl, or optionally substituted 5- to 6-membered heterocycloalkyl; 
 Y 4  is hydrogen, halo, optionally substituted C 1 -C 6  alkyl, optionally substituted —C 3 -C 6  cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, —CN, —C(O)R 11 ; —C(O)OR 11 ; —C(O)N(R 11 )(R 12 ); —C(O)N(R 11 )S(O) 2 (R 12 ); —OR 11 , —NR 11 R 12 ; —SR 11 ; —S(O) 2 R 11 ; or —S(O) 2 N(R 11 )(R 12 ); 
 alternatively, Y 2  and Y 3  are taken together to form an optionally substituted 5-12 membered heterocyclic ring or carbocyclic ring containing 1, 2, or 3 double bonds; 
 Z 1  is CR 1 , Z 2  is CR 2 , and Z 3  is N; 
 R 1  and R 2  are each independently selected from: 
 1) hydrogen; 
 2) halogen; 
 3) —NO 2 ; 
 4) Cyano; 
 5) Optionally substituted —C 1 -C 8  alkyl; 
 6) optionally substituted —C 2 -C 8  alkenyl; 
 7) optionally substituted —C 2 -C 8  alkynyl; 
 8) optionally substituted —C 3 -C 8  cycloalkyl; 
 9) optionally substituted 3- to 12-membered heterocycloalkyl; 
 10) optionally substituted aryl; 
 11) optionally substituted arylalkyl; 
 12) optionally substituted heteroaryl; 
 13) optionally substituted heteroarylalkyl; 
 14) —SR 11 ; 
 15) —S(O) 2 R 11 ; 
 16) —S(O) 2 N(R 11 )(R 12 ); 
 17) —C(O)R 11 ; 
 18) —C(O)OR 11 ; 
 19) —C(O)N(R 11 )(R 12 ); 
 20) —C(O)N(R 11 )S(O) 2 (R 12 ); 
 21) —N(R 11 )(R 12 ); 
 22) —N(R 13 )C(O)N(R 11 )(R 12 ); 
 23) —N(R 11 )C(O)(R 12 ); 
 24) —N(R 11 )C(O) 2 (R 12 ); 
 25) —N(R 13 )S(O) 2 N(R 11 )(R 12 ); 
 26) —N(R 11 )S(O) 2 (R 12 ); 
 27) —OR 11 ; 
 28) —OC(O)R 11 ; 
 29) —OC(O)OR 11 ; and 
 30) —OC(O)N(R 11 )(R 12 ); and 
 R 11 , R 12 , and R 13 , are each independently selected from hydrogen, optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 3 -C 8  cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; alternatively, R 11  and R 12  are taken together with the nitrogen atom to which they attached to form an optionally substituted 3-8 membered heterocyclic containing 0, 1, 2, or 3 double bonds. 
 
     
     
       2. The compound of  claim 1 , wherein R 1  and R 2  are each independently selected from one of the following by removal of a hydrogen atom: 
       
         
           
           
               
               
           
         
       
       wherein each of these groups is optionally substituted with one or two groups selected from halo, CN, —OR 11 , —NR 11 R 12 , optionally substituted C 1 -C 6  alkyl, and optionally substituted 3- to 8-membered heterocyclic; and R 11  and R 12  are as defined in  claim 1 . 
     
     
       3. The compound of  claim 1 , represented by Formula (IV-1) or Formula (IV-2), or a pharmaceutically acceptable salt, N-oxide, or ester thereof: 
       
         
           
           
               
               
           
         
       
       wherein Y 1 , Y 2 , Y 3 , Y 4 , Z 1 , Z 2 , and Z3 are as defined in  claim 1 . 
     
     
       4. A compound of  claim 1 , represented by Formula (IX-3) or Formula (IX-6), or a pharmaceutically acceptable salt, N-oxide, or ester thereof: 
       
         
           
           
               
               
           
         
       
       wherein Y 1 , Y 2 , R 1 , and R 2  are as defined in  claim 1 . 
     
     
       5. The compound of  claim 1 , represented by one of Formulae (XVIII-4) to (XVIII-6), or a pharmaceutically acceptable salt, N-oxide, or ester thereof: 
       
         
           
           
               
               
           
         
       
       wherein R 22  and R 23  are each independently selected from halo, CN, —OR 11 , —NR 11 R 12 , and optionally substituted C 1 -C 6  alkyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, or 4; and R 11 , R 12 , Y 1 , Y 2 , Y 3 , Y 4 , Q 3 , and Q 4  are as defined in  claim 1 . 
     
     
       6. The compound of  claim 1 , represented by one of Formulae (XX-4) to (XX-6), or a pharmaceutically acceptable salt, N-oxide, or ester thereof: 
       
         
           
           
               
               
           
         
       
       wherein R 22  and R 23  are each independently selected from halo, CN, —OR 11 , —NR 11 R 12 , and optionally substituted C 1 -C 6  alkyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, or 4; and R 11 , R 12 , Y 1 , Q 3 , and Q 4  are as defined in  claim 1 . 
     
     
       7. The compound of  claim 1 , selected from the compounds set forth below or a pharmaceutically acceptable salt, N-oxide, or ester thereof: 
       
         
           
                 
                 
                 
                 
               
                     
                 
                   Compound 
                   Structure 
                   Compound 
                   Structure 
                 
                     
                 
                   1 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   2 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   3 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   4 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   5 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   6 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   7 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   8 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   9 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
       8. A pharmaceutical composition, comprising a compound according to  claim 1 , in combination with a pharmaceutically acceptable carrier or excipient. 
     
     
       9. A method of treating an HBV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a combination of compounds according to  claim 1 .